Abstract Mycobacterium tuberculosis (Mtb) causes pulmonary tuberculosis (TB) in humans. In 2015 alone,10.4 million new cases were reported, leading to approximately 1.4 million deaths. There are no effective vaccines for TB and only sub-optimal chemotherapeutics exist. Mtb, after a period of intracellular replication and inhibition of host cell apoptosis, leaves the phagosome and triggers cell lysis in order to exit the host cell. There is a gap in our understanding of how Mtb exploits host cell signaling in order to mediate these events. We have discovered a novel transcriptional repressor, Rv3167c, that is important for suppression of phagosomal escape, host cell necrosis and of macroautophagy (autophagy) induction. This activity is mediated via suppression of gene transcription of genes encoding for synthesis and transport of the outer cell membrane lipid phthiocerol dimycocerosates (PDIM). In the current application we propose to utilize a unique set of Mtb mutants discovered in our lab to elucidate the molecular mechanisms of Mtb-mediated host cell necrosis induction. In AIM1 we will characterize the host cell necrosis and autophagy signaling pathways engaged after phagosomal exit of Mtb. AIM1.1. will test how Mtb mediates the regulation of the host kinase AKT. The Aims 1.2 and 1.3 will explore cell signaling events downstream of AKT leading to necrosis or autophagy induction, respectively. These approaches will be used to identify central signaling hubs within the signaling network that will be most interesting for host directed therapeutic approaches. In AIM2 we will characterize the relevance of host cell escape pathway for virulence of Mtb and its potential as a target for therapeutic approaches. In Aim 2.1, knock-out or knock-in mice will be used to corroborate the ex vivo findings of the importance of select host cell signaling proteins during in vivo infection. In Aim 2.2 our discovery of host cell necrosis signaling components will be exploited to test their relevance for Mtb virulence during aerosol infection of mice and thus determine their potential as novel candidates for host-targeted therapeutics using the mouse model of tuberculosis. We believe that our findings will have great translational potential since inhibition of Mtb-mediated necrosis should reduce virulence of the bacteria and decrease host lung pathology.